1. Field of the Invention
The present invention relates to a composition for prevention or treatment of a bone metabolism disorder comprising D-pinitol as an active ingredient.
2. Background of Technique
Bone supports muscles or organs of human body and protects internal organs from external impact by surrounding them. Bone is also an important part of human body, which stores not only internal calciums but also essential inorganic substances such as phosphorus or magnesium. Old bone matrix of adult is removed and replaced with new one. The balance of bone production is maintained through the repeated process of a resorption and destruction. This process is named as bone remodeling (Yamaguchi A. et al., Tanpakushitsu Kakusan Koso, 50(6 Suppl):664-669 (2005)). Turnover of bone matrix may be essential to the recovery of a subtle injury of bone generated by stress and bone growth, and to suitable maintenance of bone function (Cohen-Solal M. et al., Therapie, 58(5):391-393 (2003)).
It is known that two types of cells are associated with bone remodeling. One is osteoblast which is in charge of building bone and the other is osteoclast in charge of destroying it. The osteoblast produces RANKL (receptor activator of nuclear factor-κB ligand) and its decoy receptor, OPG (osteoprotegerin). Where RANKL is bound to RANK (receptor activator of nuclear factor-κB) on osteoclast progenitor cells, osteoclast progenitor cell become matured to osteoclast, allowing bone resorption to be occurred. However, when OPG is bound to RANKL, the binding of RANKL to RANK is blocked and resulted in the prevention of osteoclast formation and inhibition of bone resorption (Theill L E. et al., Annu Rev Immunol, 20:795-823 (2002); Wagner E F. et al., Curr Opin Genet Dev, 11:527-532 (2001)). Resorption or destruction of old bone is carried out by osteoclast derived from blood cell (hematopoietic stem cell), which gnaw a hole on bone and release a small amount of calcium into blood flow. The released calcium can be used to maintain the body function (William J. et al., Nature, 423:337-342 (2003)).
Osteoblast can reconstruct skeleton by generating rigid new bone through the process of filling the hole on bone with collagen and covering it with hydroxyapatite of calcium and phosphorus (Stains J P. et al., Birth Defects Res C Embryo Today, 75(1):72-80 (2005)). In order to maintain constant bone density, the rate of osteoclastic destruction must be same with the osteogenetic rate of bone. When the balance of bone remodeling is broken, various diseases, for example osteoporosis may be occurred (FIG. 1).
Osteoporosis is a disorder in which bone mass is reduced by various causes and the risk of bone fracture continuously increase due to the degeneration of microstructure on bone tissue. Osteoporosis is a condition in which the content of minerals (e.g., calcium) and substrates of bone has been reduced. Osteoporosis can be occurred when the activity of osteoclasis becomes superior to that of osteogenesis owing to the imbalance of bone remodeling (Iqbal M M., South Med J, 93(1): 2-18 (2000)).
The patient of osteoporosis is characterized by the rapid bone loss (2-3% per a year) at the time of the beginning of menopause. Osteoporosis is classified into two types of disease according to its cause: a postmenopausal osteoporosis in which spinal pressure and fracture risk of carpal bone are increased and secondary osteoporosis which is generated from various age-irrelevant causes such as diseases (endocrinopathy, gastrointestinal disorder, malignant tumor), drugs (adrenocortical hormone, anticancer chemotherapy, thyroid hormone, anticonvulsant, anticoagulant, methotexate, cyclosporine, GnRH, etc.), alcohol, smoking and accident (Rosep C J., N Eng J Med, 353(6):595-603 (2005); Davidson M., Clinicain Reviews, 12(4):75-82 (2002)).
Therapeutic agents for osteoporosis that act via suppressing the function of osteoclast are currently developed in two directions. The first is to develop an agent inhibiting the bone resorption process of osteoclast. A substance that can prevent the bone resorption process of differentiated osteoclasts may be directly used as a therapeutic agent of osteoporosis. The second is to investigate a substance that can inhibit the signal transduction pathway of osteoclastogenesis.
Osteoclast is differentiated from hematopoietic stem cells which reside in bone marrow like the differentiation of immune cells. Osteoclast is initially differentiated to monocyte by macrophage differentiation factors, M-CSF (macrophage-colony stimulating factor) and TRANCE (TNF-related activation induced cytokine), and finally to osteoclast by TRANCE (FIG. 2) (1-6).
Another important disease caused by the disruption of a bone remodeling balance is a bone injury due to the metastasis of cancer cells to bone. Metastasis to bone is almost always occurred in patents having breast cancer, prostate cancer or multiple myeloma (Kozlow W. et al., J Mammary Gland Biol Neoplasia, 10(2):169-180 (2005)). It is known that the survival period of these cancer patients depends on the occurrence of cancer metastasis to bone.
The Metastasis to bone observed in breast cancer patients is osteolytic metastasis in which most of bone is destroyed and is known to be occurred by stimulating the osteoclast not by direct action of breast cancer cell (Boyde A. et al., Scan Electron Microsc, 4:1537-1554 (1986)). On the other hand, metastasis to bone observed in prostate cancer is osteoblastic metastasis. It is also known that osteoblsatic metastasis has a close relation with osteolysis.
D-pinitol is known to be contained in pinewood and legumes. A pinitol-like substances of undisclosed structure extracted from Bougainvillea spectabilis was found to lower the blood glucose level of both normal and alloxan-treated insulin-deficient mice at a minimum dosage of 0.01 g/kg (Narayanan, C. R., Joshi, D. D., Mujumdar, A. M., Dhekne, V. V. 1987. Pinitol—A new antidiabetic compound from the leaves of Bougainvillea spectabilis. Current Science 56: 139141). U.S. Pat. No. 5,827,896 proposed use of D-pinitol and its derivatives in diabetes treatment as metabolism disorder. However, it has not been known yet that D-pinitol has efficacy of treatment for diseases associated with bone.
Throughout this application, various publications and patents are referred and citations are provided in parentheses. The disclosures of these publications and patents in their entities are hereby incorporated by references into this application in order to fully describe this invention and the state of the art to which this invention pertains.